An estimated 8-12 million Americans suffer from peripheral artery disease (PAD), leading to significant morbidity and mortality. Despite current available medical and surgical therapies, patients with PAD continue to be at an unacceptably high risk for cardiovascular events and death. Accordingly, interventions to improve morbidity and mortality are critical. Emerging research demonstrates the inter-related effects of inflammation, vascular function and outcomes in PAD. Lifestyle modifications, including exercise and diet, may potentially improve symptoms, as well as modulate factors that influence disease progression and long-term outcomes in these patients. Fish oil has long been recognized to have beneficial effects on cardiovascular health, despite recent controversy. Recent studies have emerged on the role of n-3 polyunsaturated fatty acids (PUFA) present in fish oil in the termination of inflammation. This role offers new perspectives on the benefits of fish oil consumption. Furthermore, our group recently demonstrated that the omega-3 index, a measure of n-3 PUFA content in red blood cells, is inversely related to inflammation in patients with PAD, and others have shown that n-3 PUFA supplementation can improve vascular function. Hence, overall evidence suggests that fish oil could play a key role in the regulation of inflammatory processes and vascular dysfunction that characterize PAD. My long-term goal is to increase our understanding of how nutritional and lifestyle modifications can reduce the burden of disease in PAD. Accordingly, my goal with the present study is to determine if high-dose n-3 PUFA oral supplementation will improve systemic inflammation, vascular function, and the walking ability of patients with PAD. This will be evaluated using a double-blind, randomized, placebo-controlled trial of 70 patients aged e 50 with PAD receiving 4.4 g/day of n-3 PUFA for 3 months. Specific measurements will include markers of both inflammation and termination of inflammation, measures of vascular function, and a walking test. The study proposed here has the potential to provide important new insights on the role of nutritional interventions in PAD, as well as to improve our understanding of the effects of fish oil supplementation in cardiovascular diseases. It will support the goal of the National Heart, Lung and Blood Institute of reducing the burden of heart, lung, and blood diseases worldwide. The training plan and study protocol presented here are designed to advance my skills as an independent clinical trialist, supported by a multidisciplinary team of mentors with broad expertise in clinical trials, surgery, biostatistics, vascular biology, and molecular biology. The research will take place at the San Francisco Veterans Affairs Medical Center (SFVAMC), one of the most funded and scientifically knowledgeable VA centers in the United States. Furthermore, I will have access to institutional support and resources from both the SFVAMC and UCSF. The training plan, mentorship, and scientific environment will provide me with the resources necessary for the successful completion of this project, and place me on the path to become an independent investigator and leader in my field.